Diabetes mellitus (DM) describes several syndromes of abnormal carbohydrate metabolism, characterized by hyperglycemia. It is associated with a relative or absolute impairment in insulin secretion, along with varying degrees of peripheral resistance to the action of insulin. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
There are two major forms of diabetes: Type 1 diabetes, also referred to as insulin-dependent diabetes; and Type 2 diabetes, also referred to as noninsulin dependent diabetes. When inadequate amounts of insulin are present to compensate for insulin resistance and adequately control glucose, a state of impaired glucose tolerance develops. In a significant number of individuals, the plasma glucose level rises, resulting in the clinical state of diabetes. Insulin stimulates glucose uptake by skeletal muscle and adipose tissues primarily through translocation of the glucose transporter 4 from the intracellular storage sites of the cell surface
Diabetes is often associated with high fat diet and obesity. The majority of diabetic patients are treated either with hypoglycemic agents which act by stimulating release of insulin from beta cells, or with agents that enhance the tissue sensitivity of the patients towards insulin, or with insulin.
Multiple endocrine neoplasia type 1 (MEN1) is a dominantly inherited tumor syndrome that results from the mutation of the tumor suppressor gene Men1, which encodes menin. Menin interacts with multiple proteins that play critical roles in the regulation of cell proliferation, including JunD, Smad 3, and activator of S-phase kinase. Activator of S-phase kinase is the crucial regulatory factor for protein kinase cdc7 that is required for initiation of DNA replication and menin functionally represses the activity of activator of S-phase kinase. In addition, menin interacts with a protein complex containing the mixed lineage leukemia protein and up-regulates transcription of various target genes, including the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p18Ink4c, in transformed fibroblasts and insulinoma cells. Whereas these observations provide a potential mechanistic link between menin and cell cycle regulation, a direct link between menin function and cell cycle progression has not been established. An obstacle to answering this question has been the lack of synchronizable cells in which Men1 can be conditionally inactivated in vitro so that the effect of Men1 deletion on the cell cycle progression can be examined.
Mouse models have greatly increased understanding of molecular pathology of the MEN1 syndrome. Tumors derived from mice heterozygous for Men1 display loss of heterozygosity, confirming the role of menin as a bona fide tumor suppressor. Tumors arise in the parathyroid, pituitary, and pancreatic islet cells from the mice in which Men1 is conditionally inactivated in these respective organs, establishing an important role for menin in suppressing tumor development in endocrine organs. However, because the excision of Men1 is not under temporal control in these mice, it is challenging to study the acute effects of deletion of Men1 on proliferation of pancreatic islet cells. Thus, although tumor cells in insulinomas of the mice display enhanced cell proliferation as shown by 5′-bromo-2′-deoxyuridine-5′-triphosphate (BrdUrd) uptake, it is difficult to determine how soon after Men1 deletion, increased islet cell proliferation occurs. If increased islet proliferation is an acute consequence of Men1 deletion, then this would suggest that loss of menin-mediated repression of cell proliferation is at least in part responsible for the early events of islet cell proliferation observed in MEN1.
While current drug therapy may provide reduction in blood sugar, it often promotes obesity as well as, in the long term, may lead to accelerated exhaustion of the endogenous production of insulin in diabetics Accordingly, a need exists for improved methods and compositions for treating various forms of diabetes.